Alcohol use disorders in the United States (US) account for about 1 death every 5 minutes including 32% of all traffic fatalities, an average of one fatality related to alcohol every 39 minutes. Alcohol liver disease (ALD) is often present in alcohol dependent (AD) patients. Treatments for ALD have limited success when drinking continues. Cessation of alcohol consumption or a significant reduction in alcohol intake improves histology and survival of patients with any stage of ALD. While alcohol abstinence may not be sufficient to provide a total recovery of ALD, patients with uncomplicated ALD have a 5-year survival of almost 90% if they stop drinking. Consequently, abstinence is the most important therapeutic intervention for patients with ALD. When combined with psychosocial treatments, currently approved medications can improve outcomes for some AD individuals; however, these treatments are unsuccessful for many others. One of the limiting factors that must be taken into consideration when using currently approved medications such as disulfiram or naltrexone is liver function. Given their hepatic metabolism, disulfiram or naltrexone both increase the risk of hepatotoxicity in AD individuals. Therefore, a pharmacotherapy that is effective for AD, that is safe for the liver and able to recover alcohol-related liver damage thereby improving liver function, would be an ideal medication. However as of now, no drug has been found to provide all of these benefits to AD individuals. We propose therefore to test metadoxine (MTDX) that we hypothesize is significantly beneficial for the treatment of alcoholism and ALD. Metadoxine is currently approved in Europe for acute and chronic alcohol intoxication but has never been tested in the US. Furthermore, MTDX is used in Europe to treat ALD. Our group and others have shown preliminary evidence that MTDX reduces alcohol consumption in AD individuals. If the role of MTDX in reducing alcohol consumption and improve liver function is confirmed by a rigorous study design, then MTDX might represent a truly innovative pharmacotherapy for AD, given the potential to be used for AD individuals with ALD. However until this proposal, MTDX has never been investigated as a treatment for AD able to reduce both alcohol consumption and improve alcohol-related liver damage via a double-blind placebo- controlled study. This project therefore proposes to conduct a 12-week (followed by a 3-month follow-up), double-blind, placebo-controlled, between-subject randomized clinical trial with MTDX (500mg t.i.d.) in AD individuals. This project will randomize 83 AD individuals who also have a diagnosis of ALD. Given our previous experience in using MTDX, we propose this innovative R21 grant to explore MTDX's efficacy in reducing or stopping alcohol consumption in AD individuals with evidence of alcohol-related liver damage. Our long-term goal is to provide the first safe and effective treatment option for both AD and ALD. PUBLIC HEALTH RELEVANCE: Alcohol use disorders account for 100,000 excess deaths per year and causes serious morbidity and mortality, increased health care costs and lost work hours. Thus, there exists a substantial need for discovering new, more effective treatments for alcohol use disorders. Furthermore, alcohol liver disease (ALD) represents a significant medical problem often present in individuals with alcohol dependence (AD). This project proposes testing a novel pharmacotherapy, metadoxine, as a medication potentially effective in treating both AD and ALD. Better characterization of this pharmacological approach, by studying the medication metadoxine, may lead to a novel pharmacotherapy able to simultaneously treat AD and ALD.